Our laboratory uses a variety of mouse models of cancer to study the fundamental aspects of oncogenesis that have become important features of new therapeutic approaches to cancer. The questions we will pursue under the terms of this award include: At which stages of a developmental lineage are cells susceptible to oncogenic mutations? What determines whether a cancer cell is dependent on an inciting oncogene for continued viability? What is the role of apoptotic signaling pathways in the phenomenon of oncogene-dependence? And what do answers to such questions imply for the development of more effective therapies? The proposed studies will employ new and existing mouse models of cancer affecting the hematopoietic system (the myeloid and B cell lineages) and the pancreas and a variety of known oncogenes and tumor suppressor genes. In particular, we will explore the role of the anti-apoptotic members of the BCL family in oncogene cooperation and oncogene dependence; establish the stage-specific vulnerability of the B cell lineage to Myc-mediated lymphomagenesis; and determine the limitations to exercising the full oncogenic potential of polyoma middle T antigen in pancreatic beta cells. The implications of these studies for understanding human carcinogenesis and developing new therapeutic approaches to human cancers will be vigorously explored. The three post-doctoral fellows who will be performing most of the work under the terms of this award are well-trained for the projects we propose here. Dr. Levi Beverly has developed mouse models of leukemia as a graduate student with Dr. Anthony Capobianco (at the University of Cincinnati and the Wistar Institute) and is highly skilled in the growth and analysis of hematopoietic cells; he will be leading the project described in Section 2.A. Dr. Arun Unni did his graduate work on innate immunity with Dr. Ruslan Medzhitov at Yale, has intimate knowledge of the B cell lineage, and will have primary responsibility for the experiments outlined in Section 2.B. Dr. Nancy Du received her Ph.D. with Dr. Bruce Stillman at Cold Spring Harbor Laboratory for studies of a multifunctional yeast protein; during her post-doctoral work here, she has studied several aspects of pancreatic carcinogenesis, in part with support from our current MMHCC award, and she built and will continue to study the new mouse models that are described in Section 2. C.